Method of forming a nitinol stent

ABSTRACT

A method of a forming a hollow, drug-eluting nitinol stent includes shaping a composite wire into a stent pattern, wherein the composite wire comprises an inner member, a nitinol intermediate member, and an outer member. After the composite wire is shaped into the stent pattern, the composite wire is heat treated to set the nitinol intermediate member in the stent pattern. After heat treatment, the composite wire is processed to remove the outer member and the inner member without adversely affecting the intermediate member. Openings may be provided through the intermediate member and the lumen of the intermediate member may be filled with a substance to be eluted through the openings.

FIELD OF THE INVENTION

The present invention relates to methods of making stents, and inparticular, to methods of making stents from nitinol wires.

BACKGROUND OF THE INVENTION

Drug-eluting implantable medical devices have become popular in recenttimes for their ability to perform their primary function (such asstructural support) and their ability to medically treat the area inwhich they are implanted. Further, stents made from shape memorymaterials, particularly nitinol, have become popular.

Stents formed from nitinol include many characteristics desirable in aneffective stent. Nitinol is a nickel-titanium alloy generally containingapproximately 55-56% nickel and 44-45% titanium. Nitinol was developedby the Naval Ordinance Laboratory and receives its name from itscomponent parts and the Naval Ordinance Laboratory(Nickel/Titanium/Naval Ordinance Laboratory). Specifically, stentsformed from nitinol, with or without special coatings, have been foundto be chemically and biologically inert and to inhibit thrombusformation. Nitinol, under certain conditions, is also superelastic,which allows it to withstand extensive deformation and still resume itsoriginal shape. Furthermore, nitinol possesses shape memory, i.e., themetal “remembers” a specific shape fixed during a particular heattreatment and can resort to that shape under proper conditions.

The superelasticity of nitinol and its shape memory characteristicsmakes it possible to fabricate a stent having the desired shape anddimensions. Once formed, the stent can be temporarily deformed into amuch narrower shape for insertion into the body. Once in place, thestent can be made to resume its desired shape and dimensions. Certainalloys of nickel and titanium can be made which are plastic attemperatures below about 30° C. and are elastic at body temperaturesabove 35° C. Such alloys are widely used for the production of stentsfor medical use since these nitinol stents are able to resume theirdesired shape at normal body temperature without the need toartificially heat the stent

While using nitinol for stents is desirable, nitinol material presentssome difficulties in the formation of the stent itself. Nitinolmaterials in either the cold worked or heat-treated state can be easilysheared or stamped, but they are difficult to form to an accurategeometry, whether by forming wire shapes or die pressing. Thus, manynitinol stents are formed from a nitinol tube that is laser cut to theshape of a stent, sometimes also known as a tubular slotted stent.However, many stents are formed by manipulating a wire into a desiredstent shape. When forming such a stent from a nitinol wire, complicatedor specific design fixtures are required to hold the nitinol wire in thedesired pattern throughout the heat setting, or heat treatment, processcycle. Typical process steps when forming a nitinol wire to be used as astent include: conforming the nitinol wire to the geometry of thefixture; placing the nitinol wire and fixture into a “furnace” or otherheating device for a set temperature and duration; removing the nitinolwire and fixture from the heating device and quenching (flash cooling);and removing the nitinol wire from the fixture. Custom fixtures may berequired for each particular stent design. It is also often difficult togenerate a cost effective fixture for simple and complicated stentpatterns. Simpler wire forming methods available for stents made fromother materials, where controlled plastic deformation of the wire intothe desired shape allows for the wire to hold its shape through furtherprocessing, are generally not available for use with nitinol wires. Forexample, and not by way of limitation, methods and devices for creatingwaveforms in a wire described in U.S. Application Publication Nos.2010/0269950 to Hoff et al. and 2011/0070358 to Mauch et al., andco-pending U.S. application Ser. Nos. 13/191,134 and 13/190,775, filedJul. 26, 2011, may not effectively be used to form nitinol wire stents.

Thus, there is a need for an improved method for forming a stent from anitinol wire, and in particular, and improved method of forming a stentwith a hollow nitinol wire.

SUMMARY OF INVENTION

Embodiments hereof relate to a method of forming a nitinol hollow wirestent. A composite wire including a core member, an intermediate nitinolmember, and an outer member is shaped into a stent pattern. The outermember of the composite wire holds the intermediate nitinol member inthe stent pattern until a heat treatment step is applied. The compositewire is heat treated to set the stent pattern into the intermediatenitinol member of the composite wire. The composite wire is thenprocessed such that the outer member is removed from around theintermediate member without adversely affecting the intermediate member,such as by chemical etching. Openings may be provided through theintermediate member to a lumen of the intermediate member, or to thecore member of the composite wire. The composite wire may also beprocessed to remove the core member from the lumen of the intermediatemember without adversely affecting the intermediate member, and thelumen may be filled with a biologically or pharmacologically activesubstance.

Embodiments hereof also relate to a method of forming a stent with asolid nitinol wire. A composite wire including a solid nitinol innermember and an outer member is shaped into a stent pattern. The outermember of the composite wire holds the inner nitinol member in the stentpattern until the heat treatment step is completed. The composite wireis heat treated to set the nitinol inner member in the stent pattern.The composite wire is then processed such that the outer member isremoved from around the inner member without adversely affecting theintermediate member, such as by chemical etching, thus leaving the solidnitinol inner member in the stent pattern.

BRIEF DESCRIPTION OF DRAWINGS

The foregoing and other features and advantages of the invention will beapparent from the following description of the invention as illustratedin the accompanying drawings. The accompanying drawings, which areincorporated herein and form a part of the specification, further serveto explain the principles of the invention and to enable a personskilled in the pertinent art to make and use the invention. The drawingsare not to scale.

FIG. 1 is a schematic illustration of an exemplary stent in accordancewith an embodiment hereof.

FIG. 2 is a cross-sectional view taken along line 2-2 of FIG. 1.

FIG. 3 is a longitudinal cross-section of an end of the wire of thestent of FIG. 1.

FIG. 4 is a schematic illustration of a composite wire including a coremember, an intermediate member, and an outer member.

FIGS. 5-9 are cross-sectional views of the composite wire of FIG. 4 atvarious stages of an embodiment of a method of forming a hollow nitinolwire stent.

FIG. 10 is flow chart illustrating an embodiment of a method of forminga hollow Nitinol wire stent.

FIG. 11 is a schematic illustration of an exemplary stent in accordancewith an embodiment hereof.

FIG. 12 is a cross-sectional view taken along line 12-12 of FIG. 11.

FIG. 13 is a schematic illustration of a composite wire including anitinol core member and an outer member.

FIG. 14 is a cross-sectional view of the composite wire of FIG. 13.

FIG. 15 is flow chart illustrating an embodiment of a method of forminga nitinol wire stent.

FIG. 16 is a schematic illustration of a stent in accordance with anembodiment hereof.

FIG. 17 is a cross-section view taken along line 17-17 of FIG. 16.

FIG. 18 is a schematic illustration of a composite within including acore member and a nitinol outer member.

FIG. 19 is a flow chart illustrating steps in an embodiment of a methodof forming a hollow nitinol wire stent.

FIGS. 20-23 are cross-sectional views of a composite wire of FIG. 18 atvarious stages of the method of FIG. 19.

DETAILED DESCRIPTION OF THE INVENTION

Specific embodiments of the present invention are now described withreference to the figures, where like reference numbers indicateidentical or functionally similar elements.

An embodiment of a stent 100 disclosed herein is shown in FIGS. 1-3. Inparticular, stent 100 is formed from a hollow wire 102, in particular, ahollow nitinol wire 102. The term “wire” as used herein means anelongated element or filament or group of elongated elements orfilaments and is not limited to a particular cross-sectional shape ormaterial, unless so specified. In the embodiment shown in FIG. 1, hollowwire 102 is formed into a series of generally sinusoidal waveformsincluding generally straight segments or struts 106 joined by bentsegments or crowns 108. The wire with the waveforms formed therein ishelically wrapped to form a tube, as shown in FIG. 1. In the embodimentshown in FIG. 1, selected crowns 108 of longitudinally adjacentsinusoids may be joined by, for example, fusion points 110. Theinvention hereof is not limited to the pattern shown in FIG. 1. Wire 102of stent 100 can be formed into any pattern suitable for use as a stent.For example, and not by way of limitation, wire 102 of stent 100 can beformed into patterns disclosed in U.S. Pat. No. 4,800,882 to Gianturco,U.S. Pat. No. 4,886,062 to Wiktor, U.S. Pat. No. 5,133,732 to Wiktor,U.S. Pat. No. 5,782,903 to Wiktor, U.S. Pat. No. 6,136,023 to Boyle, andU.S. Pat. No. 5,019,090 to Pinchuk, each of which is incorporated byreference herein in its entirety. Further, instead of a single length ofwire formed into a stent pattern, a plurality of wires may be formedinto a two-dimensional waveform and wrapped into individual cylindricalelements. The cylindrical elements may then be aligned along a commonlongitudinal axis and joined to form the stent.

As shown in FIG. 2, hollow wire 102 of stent 100 allows for abiologically or pharmacologically active substance 112 to be depositedwithin the lumen 103 of hollow wire 102. Although hollow wire 102 isshown as generally having a circular cross-section, hollow wire 102 maybe generally elliptical or rectangular in cross-section. Hollow wire 102further includes cuts or openings 104 dispersed along its length topermit biologically or pharmacologically active substance 112 to bereleased from lumen 103. Openings 104 may be disposed only on struts 106of stent 100, only on crowns 108 of stent 100, or both struts 106 andcrowns 108. Openings 104 may be sized and shaped as desired to controlthe elution rate of biologically or pharmacologically active substance112 from stent 100. Larger sized openings 104 generally permit a fasterelution rate and smaller sized openings 104 generally provide a slowerelution rate. Further, the size and/or quantity of openings 104 may bevaried along stent 100 in order to vary the quantity and/or rate ofbiologically or pharmacologically active substance 112 being eluted fromstent 100 at different portions of stent 100. Openings 104 may be, forexample and not by way of limitation, 5-30 μm in diameter. Openings 104may be provided only on an outwardly facing or abluminal surface 116 ofstent 100, as shown in FIG. 2, only on the inwardly facing or luminalsurface 118 of stent 100, both surfaces, or may be provided anywherealong the circumference of wire 102. Openings 104 may have a constantdiameter through the depth or have a tapered or conical shape.

Ends 114 of wire 102 may be closed, as shown in FIG. 3. Ends 114 may beclosed by crimping excess material of wire 102 to close lumen 103.Closing ends 114 prevents drug 112 from prematurely releasing from ends114. However, closing ends 114 is not required as drug 112 may be dried,provided within a polymer matrix, enclosed within a liner (not shown),or otherwise protected from premature release from ends 114. Further,ends 114 may be welded, crimped or otherwise connected to other portionsof wire 102 such that the ends 114 are not free ends. Ends 114 mayalternatively be provided as free ends. Further, ends 114 may be sealedby not removing the core member 120 from the ends of the wire, as shownin FIG. 3.

FIGS. 4-10 show a method for forming a hollow wire stent in accordancewith an embodiment hereof. As shown in FIG. 10, step 200 is to utilize awire having an outer member, an intermediate member, and a central coremember. These types of wire are sometimes referred to as core wires,tri-layer wires, or composite wires. Composite wire 170 hereof is formedof an outer member 130, an intermediate member 102 disposed within alumen 132 of outer member 130, and an inner or core member 120 disposedwithin a lumen 103 of intermediate member 102, as shown schematically inFIG. 4. Intermediate member 102 becomes hollow wire 102 of stent 100,and thus has been labeled with the same reference number. Composite wire170 may be formed by any method known in the art, for example and not byway of limitation, a drawn filled tubing process, extrusion, cladding,material deposition, or any other suitable method. Examples of compositewires and methods of forming composite wires can be found in U.S. Pat.No. 5,630,840 to Mayer, U.S. Pat. No. 6,248,190 to Stinson, U.S. Pat.No. 6,497,709 to Heath, and U.S. Pat. No. 7,101,392 to Heath, each ofwhich is incorporated by reference herein in its entirety.

Intermediate member 102 in this embodiment is formed from nitinol.Intermediate member 102, as explained in more detail below, is thesurviving material that will become hollow wire 102 of stent 100. Outermember 130 is formed from a material that is more plastically deformablethan the nitinol material of intermediate member 102, and issufficiently stiff to hold intermediate member 102 in the stent patternuntil the heat treatment step, as described below. Further, the materialused for outer member 130 must be able to be removed by a process thatdoes not damage intermediate member 102. Similarly, core member 120 ismade of a sacrificial material that can be removed by a process thatdoes not damage the nitinol material of intermediate member 102. Coremember 120 may be the same material as outer member 130, or may be adifferent material. In one non-limiting embodiment core member 120 andouter member 130 are made from tantalum. Examples of other materials forcore member 120 and outer member 130 include, but are not limited to,tungsten (W), molybdenum (Mo), niobium (Nb), rhenium (Re), carbon (C),germanium (Ge), silicon (Si) and alloys thereof.

A cross-section of composite wire 170 is shown in FIG. 5. Intermediatemember 102 may have an outer diameter D2 in the range of 0.0025 inch to0.010 inch and wall thickness T2 in the range of 0.0005 inch or larger,depending on the application, for example, in what lumen or organ andfor what purpose the stent is to be utilized. Accordingly, core member120 may have an outer diameter D1 of 0.0005 inch to 0.0095 inch. Outermember 130 may have a thickness T3 in the range of 0.0001 inch orlarger, depending on the material used for each member of composite wire170. In one particular non-limiting example, core member 120 is madefrom tantalum and has an outer diameter D1 of 0.0020, intermediatemember 102 is made from nitinol and has a thickness T2 of 0.0025 and anouter diameter D2 of 0.0070, and outer member 130 is made from tantalumand has a thickness T3 of 0.0005 and an outer diameter D3 of 0.0080. Thevalues listed above are merely examples and other diameters andthicknesses may be used depending on, for example, the materials used,the desired stent shape, and the purpose or location of the stent.

Referring to FIG. 10, step 210 is to shape the composite wire 170 intothe stent pattern. As discussed above, the stent pattern can be thepattern shown in FIG. 1 or any other suitable pattern formed from awire. Further, although the order of all the steps is not critical, step210 must be done prior to removing outer member 130, as explained inmore detail below. However, the step of shaping the composite member 170into the stent pattern does not have to include shaping composite member170 into the final stent pattern. For example, the step 210 of shapingthe composite member 170 into a stent pattern may include only formingthe struts 106 and crowns 108 in composite wire 170, prior to the heattreating step described below. Shaping composite wire 170 into the stentpattern while outer member 130 is disposed around nitinol intermediatemember 102 and core member 120 is disposed within intermediate member102 allows for outer member 130 and core member 120 to “hold” nitinolintermediate member 102 in the stent pattern. As explained above,nitinol members generally must be held in the desired stent patternusing complicated, custom designed fixtures or jigs prior to the heattreating step. Utilizing outer member 130 and core member 120 eliminatesthe need for such complicated, custom designed fixtures or jigs. Thisholding function may be primarily accomplished by outer member 130.Thus, the step 210 of shaping composite wire 170 into the stent patterncan be performed with the same techniques used to shape conventionalstents made from stainless steel, MP35N, or other known materials. Forexample, and not by way of limitation, shaping the composite wire 170into the stent pattern shown in FIG. 1 generally includes the steps offorming composite wire 170 into a two dimensional sinusoid patternfollowed by wrapping the pattern around a mandrel, as known to thoseskilled in the art. Forming the composite wire 170 into a twodimensional waveform can be achieved, for example, using techniquesdescribed in U.S. Application Publication Nos. 2010/0269950 to Hoff etal. and 2011/0070358 to Mauch et al., and co-pending U.S. applicationSer. Nos. 13/191,134 and 13/190,775, filed Jul. 26, 2011, each of whichis incorporated in its entirety by reference herein. Other techniquesknown to those skilled in the art could also be used.

Step 220 shown in FIG. 10 is to heat treat the composite wire 170 whilein the shaped stent pattern. Heat treating the composite wire “sets” thenitinol intermediate member 102 in the stent pattern such that nitinolintermediate member 102 “remembers” the stent pattern. Accordingly, whenstent 100 with intermediate member 102 as the hollow wire thereof ismanipulated into a radially compressed configuration for insertion intoa body lumen, such as by a sleeve, the stent 100 will return to thestent configuration of FIG. 1 upon release from the sleeve, therebydeploying into the radially expanded configuration at the treatmentsite, as known to those skilled in the art. The heat treatment step 220may be performed, for example, in a furnace or similar heatingequipment. The conditions for heat treatment step 220 are known to thoseskilled in the art. For example, and not by way of limitation, compositewire 170 may be placed in a furnace at 400° C.-500° C. for 15 minutes.Appropriate temperatures and durations for the heat treatment step areknown to those skilled in the art.

When the heat treatment step 220 is completed, the composite wire 170may be removed from the furnace and any fixture to which it wasattached, for example, a mandrel. Step 230 is to process the compositewire such that outer member 130 is removed without adversely affectingthe intermediate member, such as by chemical etching. Step 230 can beperformed by any suitable process for removing outer member 130 whilepreserving intermediate member 102. In particular, subjecting compositewire 170 to xenon difluoride (XeF₂) gas at low pressure (1-6 Torr) andrelatively high temperature (approximately 150° C.) causes the xenondifluoride (XeF₂) gas to react with a tantalum (Ta) outer member 103 toform TaF₅ and Xe gases. Xenon difluoride (XeF₂) gas reacts similarlywith an outer member 130 made from tungsten, molybdenum, niobium,rhenium, carbon, germanium, and silicon. Other methods for removingouter member 130 may used, as described, for example, in U.S.Application Publication no. 2011/0008405 to Birdsall et al. and U.S.Application Publication No. 2011/0070358 to Mauch et al., whereinmethods of removing core members are described, each publishedapplication incorporated by reference herein in its entirety. Suchmethods and materials, where appropriate, can be equally applied forremoval of outer member 130. As examples, but not by way of limitation,methods such as wet chemical dissolution, solubilization, sublimation,and melting may be used with appropriate outer member/core membercombinations.

Upon completion of step 230 to etch outer member 130, intermediatemember 102 and core member 120 remain in the shape of stent 100. Across-section of composite member 170 includes intermediate member 102and core member 120, as shown in FIG. 6. Further processing steps tofinish, polish, and sterilize stent 100 may take place at this time,leaving a stent with a nitinol intermediate member 102 and a core member120. In such a situation, core member 120 may be selected to improve acharacteristic of nitinol intermediate member 102. For example, and notby way of limitation, core member 120 may be formed from a radiopaquematerial to improve radiopacity of the stent. For example, and not byway of limitation, core member 120 may be formed of tantalum orplatinum, which are considered a radiopaque material, in order toimprove the radiopacity of relatively radiolucent nitinol intermediatemember 102.

However, in order to provide a stent 100 with a hollow wire 102, asdescribed above with respect to FIGS. 1-3, further processing isrequired. In particular, step 240 is to provide openings 104 inintermediate member 102 through to lumen 103 of intermediate member 102.Openings 104 may be laser cut, drilled, etched, or otherwise provided inintermediate member 102. Step 240 need not be performed after step 230,nor before step 250, although it is preferred to be before step 250, asexplained in more detail below. If step 240 is performed after step 230,a cross-section of composite wire 170 will include intermediate member102, core member 120, and an opening 104, as shown in FIG. 7. It shouldalso be noted that step 240 of forming an opening 104 throughintermediate member 102 can be performed prior to step 230 of chemicallyetching away outer member 130. In such a situation, the opening 104 mayextend through outer member 130 and intermediate member 102 through tolumen 103 of intermediate member 102. Thus, the step 230 of chemicallyetching away outer member 130 will be combined with the step 250 ofchemically etching away core member 120, described below. In such asituation, it is preferable that the material of outer member 130 andcore member 120 may both be etched by the same etchant, such as, but notlimited to, xenon difluoride.

Step 250 is to process composite wire 170 such that core member 120 isremoved from the lumen 103 of intermediate member 102 without adverselyaffecting intermediate member 102, such as by chemical etching. Step 250can be performed by any suitable process for removing core member 120while preserving intermediate member 102. In particular, subjectingcomposite wire 170 to xenon difluoride (XeF₂) gas at low pressure (1-6Torr) and relatively high temperature (approximately 150° C.) causes thexenon difluoride (XeF₂) gas to react with a tantalum (Ta) core member120 to form TaF₅ and Xe gases, which can be exhausted from lumen 103.Xenon difluoride (XeF₂) gas reacts similarly with a core member 120 madefrom tungsten, molybdenum, niobium, rhenium, carbon, germanium, andsilicon. However, xenon difluoride (XeF₂) gas does not react with anintermediate member formed of nitinol. Other methods for removing coremember 120 may used, as described, for example, in U.S. ApplicationPublication no. 2011/0008405 to Birdsall et al. and U.S. ApplicationPublication No. 2011/0070358 to Mauch et al., each published applicationincorporated by reference herein in its entirety. As examples, but notby way of limitation, methods such as wet chemical dissolution,solubilization, sublimation, and melting may be used with appropriateintermediate member/core member combinations. Accordingly, after step250 is completed, intermediate member 102 remains and core member 120has been removed, leaving the structure shown in FIG. 8. As noted above,openings 104 do not need to be formed prior to the step of removing coremember 120 as long as there is a way to expose core member 120 to theetchant. For example, ends 114 of the wire may be open or temporaryports may for formed through intermediate member 102 to expose coremember 120 to the etchant.

After core member 120 has been removed, biologically orpharmacologically active substance 112 may be introduced into lumen 103of intermediate member 102, as shown in step 260 of FIG. 10. Thisproduces a hollow wire or intermediate member 102 with biologically orpharmacologically active substance 112 disposed in lumen 103 thereof,and openings 104 through which biologically or pharmacologically activesubstance 112 may be eluted, as shown in FIGS. 2 and 9. Filling lumen102 with a biologically or pharmacologically active substance may beaccomplished by any means known to those skilled in the art. Forexample, and not by way of limitation, methods for filling lumens ofhollow wires described in U.S. Application Publication No. 2011/0070357to Mitchell et al., each of which is incorporated by reference herein inits entirety; and co-pending U.S. application Ser. Nos. 12/884,362;12/884,451; 12/884,501; 12/884,578; 12/884,596 each filed on Sep. 17,2010, and each of which is incorporated by reference herein in itsentirety.

The biologically or pharmacologically active substance 112 may include,but is not limited to, antineoplastic, antimitotic, antiinflammatory,antiplatelet, anticoagulant, antifibrin, antithrombin,antiproliferative, antibiotic, antioxidant, and antiallergic substancesas well as combinations thereof. Examples of such antineoplastics and/orantimitotics include paclitaxel (e.g., TAXOL® by Bristol-Myers SquibbCo., Stamford, Conn.), docetaxel (e.g., Taxotere® from Aventis S. A.,Frankfurt, Germany), methotrexate, azathioprine, vincristine,vinblastine, fluorouracil, doxorubicin hydrochloride (e.g., Adriamycin®from Pharmacia & Upjohn, Peapack N.J.), and mitomycin (e.g., Mutamycin®from Bristol-Myers Squibb Co., Stamford, Conn.). Examples of suchantiplatelets, anticoagulants, antifibrin, and antithrombins includesodium heparin, low molecular weight heparins, heparinoids, hirudin,argatroban, forskolin, vapiprost, prostacyclin and prostacyclinanalogues, dextran, D-phe-pro-arg-chloromethylketone (syntheticantithrombin), dipyridamole, glycoprotein IIb/IIIa platelet membranereceptor antagonist antibody, recombinant hirudin, and thrombininhibitors such as Angiomax™ (Biogen, Inc., Cambridge, Mass.). Examplesof such cytostatic or antiproliferative agents include ABT-578 (asynthetic analog of rapamycin), rapamycin (sirolimus), zotarolimus,everolimus, angiopeptin, angiotensin converting enzyme inhibitors suchas captopril (e.g., Capoten® and Capozide® from Bristol-Myers SquibbCo., Stamford, Conn.), cilazapril or lisinopril (e.g., Prinivil® andPrinzide® from Merck & Co., Inc., Whitehouse Station, N.J.), calciumchannel blockers (such as nifedipine), colchicine, fibroblast growthfactor (FGF) antagonists, fish oil (omega 3-fatty acid), histamineantagonists, lovastatin (an inhibitor of HMG-CoA reductase, acholesterol lowering drug, brand name Mevacor® from Merck & Co., Inc.,Whitehouse Station, N.J.), monoclonal antibodies (such as those specificfor Platelet-Derived Growth Factor (PDGF) receptors), nitroprusside,phosphodiesterase inhibitors, prostaglandin inhibitors, suram in,serotonin blockers, steroids, thioprotease inhibitors,triazolopyrimidine (a PDGF antagonist), and nitric oxide. An example ofan antiallergic agent is permirolast potassium. Other biologically orpharmacologically active substances or agents that may be used includenitric oxide, alpha-interferon, genetically engineered epithelial cells,and dexamethasone. In other examples, the biologically orpharmacologically active substance is a radioactive isotope forimplantable device usage in radiotherapeutic procedures. Examples ofradioactive isotopes include, but are not limited to, phosphorus (P³²),palladium (Pd¹⁰³), cesium (Cs¹³¹), Iridium (I¹⁹²) and iodine (I¹²⁵).While the preventative and treatment properties of the foregoingbiologically or pharmacologically active substances are well-known tothose of ordinary skill in the art, the biologically orpharmacologically active substances are provided by way of example andare not meant to be limiting. Other biologically or pharmacologicallyactive substances are equally applicable for use with the disclosedmethods and compositions.

Further, a carrier may be used with the biologically orpharmacologically active substance. Examples of suitable carriersinclude, but are not limited to, urea, ethanol, acetone,tetrahydrofuran, dymethylsulfoxide, a combination thereof, or othersuitable carriers known to those skilled in the art. Still further, asurfactant may be formulated with the biologically or pharmacologicallyactive substance and the solvent to aid elution of the biologically orpharmacologically active substance.

Stent 100 may be used conventionally in blood vessels of the body tosupport such a vessel after an angioplasty procedure. It is known thatcertain biologically or pharmacologically active substances eluted fromstents may prevent restenosis or other complications associated withangioplasty or stents. Stent 100 may alternatively be used in otherorgans or tissues of the body for delivery of biologically orpharmacologically active substance to treat tumors, inflammation,nervous conditions, or other conditions that would be apparent to thoseskilled in the art.

FIGS. 11-15 show an embodiment of a stent 300 formed using a solidnitinol wire 302. In particular, stent 300 is formed from a solid wire302, as shown in FIG. 12. In the embodiment shown in FIG. 11, stent 300is formed into a series of generally sinusoidal waves includinggenerally straight segments or struts 306 joined by bent segments orcrowns 308. The generally sinusoidal pattern is formed into a tube, asshown in FIG. 11. In the embodiment shown in FIG. 11, selected crowns308 of longitudinally adjacent sinusoids may be joined by, for example,fusion points 310. The invention hereof is not limited to the patternshown in FIG. 11. Wire 302 of stent 300 can be formed into any patternsuitable for use as a stent. For example, and not by way of limitation,wire 302 can be formed into patterns disclosed in U.S. Pat. No.4,800,082 to Gianturco, U.S. Pat. No. 4,886,062 to Wiktor, U.S. Pat. No.5,133,732 to Wiktor, U.S. Pat. No. 5,782,903 to Wiktor, U.S. Pat. No.6,136,023 to Boyle, and U.S. Pat. No. 5,019,090 to Pinchuk, each ofwhich is incorporated by reference herein in its entirety.

Ends 314 of wire 302 may be free ends, as shown in FIG. 11, or may befused, crimped, or otherwise connected to other portions of wire 302, asknown to those skilled in the art. Stent 300 may be coated with abiologically or pharmacologically active substance (not shown) or may bea bare stent. A coating may be disposed on a luminal surface 316, andabluminal surface 118, or both.

As explained above, forming stents from nitinol wire is often difficultdue to complicated custom fixtures or jigs required to hold the nitinolwire in place during the heat treatment or heat setting process. In themethod described herein with respect to FIGS. 11-15, the need for suchcomplicated custom fixtures or jigs is alleviated. In particular, asshown in FIG. 15, step 400 is to utilize a wire with an outer member anda central core member. These types of wire are sometimes referred to ascore wires or composite wires. Composite wire 370 hereof is formed of anouter member 320 and an inner or core member 302 disposed within a lumen303 of outer member 320, as shown schematically in FIG. 13 and incross-section in FIG. 14. Core member 302 becomes wire 302 of stent 300,and thus has been labeled with the same reference number. Composite wire370 may be formed by any method known in the art, for example and not byway of limitation, a drawn filled tubing process, extruding the outermember over the inner member, or any other suitable method. Examples ofcore wires and methods of forming core wires can be found in U.S. Pat.No. 5,630,840 to Mayer, U.S. Pat. No. 6,248,190 to Stinson, U.S. Pat.No. 6,497,709 to Heath, and U.S. Pat. No. 7,101,392 to Heath, each ofwhich is incorporated by reference herein in its entirety.

Core member 302 is a nitinol material. Details regarding nitinol areprovided above. Core member 302, as explained in more detail below, isthe surviving material that will become wire 302. Outer member 320 maybe a material that is more plastically deformable than nitinol and issufficiently stiff to support core member 302 when composite wire 370 isdeformed such that core member 302 does not revert back to itsnon-deformed shape. In particular, outer member 320 is formed from amaterial and of a selected thickness such that after composite wire 370is bent into the stent pattern, as explained in more detail below, outermember 320 can “hold” core member 302 in the stent pattern withoutresort to complicated custom fixtures or jigs. Further, outer member 320is made of a sacrificial material that can be removed by a process thatdoes not damage the material of core member 302. Examples of materialsfor outer member 302 include, but are not limited to, tantalum (Ta),tungsten (W), molybdenum (Mo), niobium (Nb), rhenium (Re), carbon (C),germanium (Ge), silicon (Si) and alloys thereof.

A cross-section of composite wire 370 is shown in FIG. 14. Core member302 may have an outer diameter D1 in the range of 0.0025 inch to 0.0100inch depending on the application, for example, in what lumen or organand for what purpose the stent is to be utilized. Outer member 320 mayhave an outer diameter D2 in the range of 0.0030 inch to 0.0140 inch andwall thickness T2 in the range of 0.0002 to 0.0020 inch, depending onthe size of core member 302 and the material selected for outer member330. The values listed above are merely examples and other diameters andthicknesses may be used depending on, for example, the material used,the desired stent shape, and the purpose or location of the stent.

In one example, utilizing an outer member 320 formed from tantalumsurrounding the Nitinol core member 302, the core member 302 may accountfor up to 90% of the overall outer diameter D2 and the tantalum outermember 320 would have sufficient stiffness to “hold” the Nitinol coremember in place after shaping composite wire 370 into a stent pattern.In particular, the formula for stiffness is as follows:

${{stiffness} \equiv \frac{F}{\delta}} = {\frac{F}{\left( \frac{{FL}^{3}}{3\; {EI}} \right)} = {\frac{3\; {EI}}{L^{3}} = \frac{3\; {E\left( {{\frac{1}{4}\; \pi \; r_{2}^{4}} - {\frac{1}{4}\pi \; r_{1}^{4}}} \right)}}{L^{3}}}}$

where for solid circular cross section (core member 302) I=¼ πr⁴= 1/64πD1 ⁴ and for a tubular cross-section (outer member 320) I=¼πr_(o)⁴−¼πr_(i) ⁴= 1/64 πD2 ⁴− 1/64 7πD1 ⁴. Thus, stiffness is proportional toEI. The chart below shows the inner diameter D1 of nitinol core member302 as a percentage of the overall outer diameter D2 of the nitinol coremember and the tantalum outer member 320. As can be seen, even with thenitinol core member 302 taking up 90% of the overall diameter D2, theouter member 302 (outer shell) is stiffer than core member 302.

D1 as a % of D2 20% 30% 40% 50% 60% 70% 80% 90% Stiffness (EI) ofNitinol 0.06% 0.33% 1.06% 2.69% 6.01% 12.76% 28.01% 77.02% core memberas a % of stiffness of tantalum outer member

Referring back to FIG. 15, step 410 is to shape the composite wire 370into the stent pattern. As discussed above, the stent pattern can be thepattern shown in FIG. 11 or any other suitable pattern formed from awire. Further, although the order of all the steps is not critical, step410 must be done prior to removing outer member 320, as explained inmore detail below. Shaping composite wire 370 into the stent patternwhile outer member 320 surrounds core member 302 permits outer member320 to “hold” core member 302 in the stent pattern until the heattreatment step discussed below is completed. This alleviates the needfor complicated custom fixtures or jigs to hold nitinol core member 302in the stent pattern during the heat treatment step. Shaping thecomposite wire 370 into the stent pattern shown in FIG. 11 generallyincludes the steps of forming composite wire 370 into a two dimensionalwaveform or sinusoid pattern followed by wrapping the pattern around amandrel, as known to those skilled in the art. Forming the compositewire 370 into a two dimensional waveform can be achieved, for example,using techniques described in U.S. Application Publication Nos.2010/0269950 to Hoff et al. and 2011/0070358 to Mauch et al., andco-pending U.S. application Ser. Nos. 13/191,134 and 13/190,775, filedJul. 26, 2011, each of which is incorporated in its entirety byreference herein. Other techniques known to those skilled in the artcould also be used.

Step 420 shown in FIG. 15 is to heat treat the composite wire 370 whilein the shaped stent pattern. Heat treating the composite wire “sets” thenitinol core member 302 in the stent pattern such that nitinol coremember 302 “remembers” the stent pattern. Accordingly, when stent 300with core member 302 as the wire thereof is manipulated into a radiallycompressed configuration for insertion into a body lumen, such as by asleeve, the stent 300 will return to the stent configuration of FIG. 11upon release from the sleeve, thereby deploying to the radially expandedconfiguration at the treatment site, as known to those skilled in theart. The heat treatment step 420 may be performed, for example, in afurnace or similar heating equipment. The conditions for heat treatmentstep 420 are known to those skilled in the art. For example, and not byway of limitation, composite wire 370 may be placed in a furnace at 400°C.-500° C. for 15 minutes. Appropriate temperatures and durations forthe heat treatment step are known to those skilled in the art.

When the heat treatment step 420 is completed, the composite wire 370may be removed from the furnace and any fixture to which it wasattached, for example, a mandrel. Step 430 is to process composite wire370 such that outer member 320 is removed from around core member 302without adversely affecting core member 302, such as by chemicaletching. Step 430 can be performed by any suitable process for removingouter member 320 while preserving core member 302. In particular,subjecting composite wire 370 formed of a nitinol core member 302 and atantalum outer member 302 to xenon difluoride (XeF₂) gas at low pressure(1-6 Torr) and relatively high temperature (approximately 150° C.)causes the xenon difluoride (XeF₂) gas to react with the tantalum outermember 302 to form TaF₅ and Xe gases. Xenon difluoride (XeF₂) gas reactssimilarly with an outer member 302 made from tungsten, molybdenum,niobium, rhenium, carbon, germanium, and silicon. Other methods forremoving outer member 320 may used, as described, for example, in U.S.Application Publication no. 2011/0008405 to Birdsall et al. and U.S.Application Publication No. 2011/0070358 to Mauch et al., whereinmethods of removing core members are described, each publishedapplication incorporated by reference herein in its entirety. Suchmethods and materials, where appropriate, can be equally applied forremoval of outer member 320.

Removing outer member 320 leaves solid nitinol core member 302 formed ina stent pattern, as shown in FIGS. 11 and 12. Further processing ofstent 300, such as polishing, sterilizing, and other steps known tothose skilled in the art, may be performed to finish stent 300.

An embodiment of a stent 500 disclosed herein is shown in FIGS. 16-17.In particular, stent 500 is formed from a hollow wire 502, inparticular, a hollow nitinol wire 502. The term “wire” as used hereinmeans an elongated element or filament or group of elongated elements orfilaments and is not limited to a particular cross-sectional shape ormaterial, unless so specified. In the embodiment shown in FIG. 16,hollow wire 502 is formed into a series of generally sinusoidalwaveforms including generally straight segments or struts 506 joined bybent segments or crowns 508 and the wire with the waveforms formedtherein is helically wound to form a generally tubular stent 500. In theembodiment shown in FIG. 16, selected crowns 508 of longitudinallyadjacent sinusoids may be joined by, for example, fusion points 510. Theinvention hereof is not limited to the pattern shown in FIG. 16. Wire502 of stent 500 can be formed into any pattern suitable for use as astent. For example, and not by way of limitation, wire 502 of stent 500can be formed into patterns disclosed in U.S. Pat. No. 4,800,882 toGianturco, U.S. Pat. No. 4,886,062 to Wiktor, U.S. Pat. No. 5,133,732 toWiktor, U.S. Pat. No. 5,782,903 to Wiktor, U.S. Pat. No. 6,136,023 toBoyle, and U.S. Pat. No. 5,019,090 to Pinchuk, each of which isincorporated by reference herein in its entirety. Further, instead of asingle length of wire formed into a stent pattern, a plurality of wiresmay be formed into a two-dimensional waveform and wrapped intoindividual cylindrical elements. The cylindrical elements may then bealigned along a common longitudinal axis and joined to form the stent.

As shown in FIG. 17, hollow wire 502 of stent 500 allows for abiologically or pharmacologically active substance 512 to be depositedwithin the lumen 503 of hollow wire 502. Although hollow wire 502 isshown as generally having a circular cross-section, hollow wire 502 maybe generally elliptical or rectangular in cross-section. Hollow wire 502further includes cuts or openings 504 dispersed along its length topermit biologically or pharmacologically active substance 512 to bereleased from lumen 503. Openings 504 may be disposed only on struts 506of stent 500, only on crowns 508 of stent 500, or both struts 506 andcrowns 508. Openings 504 may be sized and shaped as desired to controlthe elution rate of biologically or pharmacologically active substance512 from stent 500. Larger sized openings 504 generally permit a fasterelution rate and smaller sized openings 504 generally provide a slowerelution rate. Further, the size and/or quantity of openings 504 may bevaried along stent 500 in order to vary the quantity and/or rate ofbiologically or pharmacologically active substance 512 being eluted fromstent 500 at different portions of stent 500. Openings 504 may be, forexample and not by way of limitation, 5-30 μm in diameter. Openings 504may be provided only on an outwardly facing or abluminal surface 516 ofstent 500, as shown in FIG. 17, only on the inwardly facing or luminalsurface 518 of stent 500, both surfaces, or may be provided anywherealong the circumference of wire 502. Openings 504 may have a constantdiameter through the depth or have a tapered or conical shape.

Ends 514 of wire 502 may be closed. Ends 114 may be closed by crimpingexcess material of wire 502 to close lumen 503. Closing ends 514prevents drug 512 from prematurely releasing from ends 114. However,closing ends 114 is not required as drug 512 may be dried, providedwithin a polymer matrix, enclosed within a liner (not shown), orotherwise protected from premature release from ends 514. Further, ends514 may be welded, crimped or otherwise connected to other portions ofwire 502 such that the ends 514 are not free ends. Ends 514 mayalternatively be provided as free ends. Further, ends 514 may be sealedby not removing the core member 520 from the ends of the wire.

FIGS. 18-23 show a method for forming a hollow nitinol wire stent 500 inaccordance with an embodiment hereof. As shown in FIG. 19, step 600 isto utilize a wire having an outer member 102 and a central core member120. These types of wire are sometimes referred to as core wires orcomposite wires. Composite wire 570 hereof is formed of an outer member502 and a core member 520 disposed within a lumen 503 of outer member502, as shown schematically in FIG. 18. Outer member 502 becomes hollownitinol wire 502 of stent 500, and thus has been labeled with the samereference number. Composite wire 570 may be formed by any method knownin the art, for example and not by way of limitation, a drawn filledtubing process, extrusion, cladding, material deposition, or any othersuitable method. Examples of composite wires and methods of formingcomposite wires can be found in U.S. Pat. No. 5,630,840 to Mayer, U.S.Pat. No. 6,248,190 to Stinson, U.S. Pat. No. 6,497,709 to Heath, andU.S. Pat. No. 7,101,392 to Heath, each of which is incorporated byreference herein in its entirety.

Outer member 502 in this embodiment is formed from nitinol. Outer member502, as explained in more detail below, is the surviving material thatwill become hollow nitinol wire 502 of stent 500. Core member 520 isformed from a material that is sufficiently stiff at the sizes providedto hold nitinol outer member 502 in the stent pattern until the heattreatment step, as described below. Core member 120 may also be formedof a material that is more plastically deformable than nitinol outermember 502. Further, the material used for core member 520 must be ableto be removed by a process that does not damage nitinol outer member502. In one non-limiting embodiment core member 520 is made fromtungsten. Examples of other materials for core member 520 include, butare not limited to, tantalum, molybdenum, rhenium, and alloys thereof.

A cross-section of composite wire 570 is shown in FIG. 20. Outer member502 may have an outer diameter D2 in the range of 0.0025 inch to 0.010inch and wall thickness T in the range of 0.0005 inch or larger,depending on the application, for example, in what lumen or organ andfor what purpose the stent is to be utilized. Accordingly, core member520 may have an outer diameter D1 of 0.0005 inch to 0.0095 inch. In oneparticular non-limiting example, core member 520 is made from tungstenand has an outer diameter D1 of 0.0050 and outer member 502 is made fromnitinol and has a thickness T of 0.0010 and an outer diameter D2 of0.0070. The values listed above are merely examples and other diametersand thicknesses may be used depending on, for example, the materialsused, the desired stent shape, and the purpose or location of the stent.

E _(core) I _(core) >E _(outer) I _(outer)

E _(core) D ₁ ⁴ >E _(outer)(D ₂ ⁴ −D ₁ ⁴)

-   -   where E_(outer) would be the modulus of elasticity of Nitinol        and E_(core) would be the modulus of elasticity of the inner        core material

Referring to FIG. 19, step 610 is to shape the composite wire 570 intothe stent pattern. As discussed above, the stent pattern can be thepattern shown in FIG. 16 or any other suitable pattern formed from awire. Further, although the order of all the steps is not critical, step610 must be done prior to removing core member 520, as explained in moredetail below. However, the step of shaping the composite member 570 intothe stent pattern does not have to include shaping composite member 570into the final stent pattern. For example, the step 610 of shaping thecomposite member 570 into a stent pattern may include only forming thestruts 506 and crowns 508 in composite wire 570, prior to the heattreating step described below. Shaping composite wire 570 into the stentpattern while core member 520 is disposed in the lumen of nitinol outermember 502 allows for core member 520 to “hold” nitinol outer member 502in the stent pattern prior to an during the heat treating step describedbelow. As explained above, nitinol members generally must be held in thedesired stent pattern using complicated, custom designed fixtures orjigs prior to the heat treating step. Utilizing core member 520eliminates the need for such complicated, custom designed fixtures orjigs. Thus, the step 610 of shaping composite wire 570 into the stentpattern can be performed with the same techniques used to shapeconventional stents made from stainless steel, MP35N, or other knownmaterials. For example, and not by way of limitation, shaping thecomposite wire 570 into the stent pattern shown in FIG. 16 generallyincludes the steps of forming composite wire 570 into a two dimensionalsinusoid pattern followed by wrapping the pattern around a mandrel, asknown to those skilled in the art. Forming the composite wire 570 into atwo dimensional waveform can be achieved, for example, using techniquesdescribed in U.S. Application Publication Nos. 2010/0269950 to Hoff etal. and 2011/0070358 to Mauch et al., and co-pending U.S. applicationSer. Nos. 13/191,134 and 13/190,775, filed Jul. 26, 2011, each of whichis incorporated in its entirety by reference herein. Other techniquesknown to those skilled in the art could also be used.

Step 620 shown in FIG. 19 is to heat treat the composite wire 570 whilein the shaped stent pattern. Heat treating the composite wire “sets” thenitinol outer member 502 in the stent pattern such that nitinol outermember 502 “remembers” the stent pattern. Accordingly, when stent 500with nitinol outer member 502 as the hollow wire thereof is manipulatedinto a radially compressed configuration for insertion into a bodylumen, such as by a sleeve, the stent 500 will return to the stentconfiguration of FIG. 16 upon release from the sleeve, thereby deployinginto the radially expanded configuration at the treatment site, as knownto those skilled in the art. The heat treatment step 620 may beperformed, for example, in a furnace or similar heating equipment. Theconditions for heat treatment step 620 are known to those skilled in theart. For example, and not by way of limitation, composite wire 570 maybe placed in a furnace at 400° C.-500° C. for 15 minutes. Appropriatetemperatures and durations for the heat treatment step are known tothose skilled in the art.

When the heat treatment step 620 is completed, the composite wire 570may be removed from the furnace and any fixture to which it wasattached, for example, a mandrel. Step 630 is to provide openings 504 innitinol outer member 502 through to lumen 503 of nitinol outer member502. Openings 504 may be laser cut, drilled, etched, or otherwiseprovided in outer member 502. Step 630 need not be performed after step620, nor before step 640, although it is preferred to be before step640, as explained in more detail below. If step 630 is performed afterstep 620, a cross-section of composite wire 570 will include outermember 502, core member 520, and an opening 504, as shown in FIG. 21. Itshould also be noted that step 630 of forming openings 504 through outermember 502 can be performed prior to step 610 of shaping the compositewire 570 into the stent pattern.

Step 640 is to process composite wire 570 such that core member 520 isremoved from the lumen 503 of outer member 502 without adverselyaffecting outer member 502, such as by chemical etching. Step 640 can beperformed by any suitable process for removing core member 520 whilepreserving outer member 502. In particular, subjecting composite wire570 to xenon difluoride (XeF₂) gas at low pressure (1-6 Torr) andrelatively high temperature (approximately 150° C.) causes the xenondifluoride (XeF₂) gas to react with a tungsten core member 520 to formTaF₅ and Xe gases, which can be exhausted from lumen 103. Xenondifluoride (XeF₂) gas reacts similarly with a core member 120 made fromtantalum, molybdenum, rhenium, and alloys thereof. However, xenondifluoride (XeF₂) gas does not react with an intermediate member formedof nitinol. Other methods for removing core member 520 may used, asdescribed, for example, in U.S. Application Publication no. 2011/0008405to Birdsall et al. and U.S. Application Publication No. 2011/0070358 toMauch et al., each published application incorporated by referenceherein in its entirety. As examples, but not by way of limitation,methods such as wet chemical dissolution, solubilization, sublimation,and melting may be used with appropriate outer member/core membercombinations. Accordingly, after step 640 is completed, outer member 502remains and core member 520 has been removed, leaving the structureshown in FIG. 22. As noted above, openings 504 do not need to be formedprior to the step of removing core member 520 as long as there is a wayto expose core member 520 to the etchant. For example, ends 514 of thewire may be open or temporary ports may be formed through outer member502 to expose core member 520 to the etchant.

After core member 520 has been removed, biologically orpharmacologically active substance 512 may be introduced into lumen 503of outer member 502, as shown in step 650 of FIG. 19. This produces ahollow wire or outer member 502 with biologically or pharmacologicallyactive substance 512 disposed in lumen 503 thereof, and openings 504through which biologically or pharmacologically active substance 512 maybe eluted, as shown in FIGS. 17 and 23. Filling lumen 503 with abiologically or pharmacologically active substance may be accomplishedby any means known to those skilled in the art. For example, and not byway of limitation, methods for filling lumens of hollow wires describedin U.S. Application Publication No. 2011/0070357 to Mitchell et al.,which is incorporated by reference herein in its entirety; andco-pending U.S. application Ser. Nos. 12/884,362; 12/884,451;12/884,501; 12/884,578; 12/884,596 each filed on Sep. 17, 2010, and eachof which is incorporated by reference herein in its entirety.

The biologically or pharmacologically active substance 512 may include,but is not limited to, antineoplastic, antimitotic, antiinflammatory,antiplatelet, anticoagulant, antifibrin, antithrombin,antiproliferative, antibiotic, antioxidant, and antiallergic substancesas well as combinations thereof. Examples of such antineoplastics and/orantimitotics include paclitaxel (e.g., TAXOL® by Bristol-Myers SquibbCo., Stamford, Conn.), docetaxel (e.g., Taxotere® from Aventis S. A.,Frankfurt, Germany), methotrexate, azathioprine, vincristine,vinblastine, fluorouracil, doxorubicin hydrochloride (e.g., Adriamycin®from Pharmacia & Upjohn, Peapack N.J.), and mitomycin (e.g., Mutamycin®from Bristol-Myers Squibb Co., Stamford, Conn.). Examples of suchantiplatelets, anticoagulants, antifibrin, and antithrombins includesodium heparin, low molecular weight heparins, heparinoids, hirudin,argatroban, forskolin, vapiprost, prostacyclin and prostacyclinanalogues, dextran, D-phe-pro-arg-chloromethylketone (syntheticantithrombin), dipyridamole, glycoprotein IIb/IIIa platelet membranereceptor antagonist antibody, recombinant hirudin, and thrombininhibitors such as Angiomax™ (Biogen, Inc., Cambridge, Mass.). Examplesof such cytostatic or antiproliferative agents include ABT-578 (asynthetic analog of rapamycin), rapamycin (sirolimus), zotarolimus,everolimus, angiopeptin, angiotensin converting enzyme inhibitors suchas captopril (e.g., Capoten® and Capozide® from Bristol-Myers SquibbCo., Stamford, Conn.), cilazapril or lisinopril (e.g., Prinivil® andPrinzide® from Merck & Co., Inc., Whitehouse Station, N.J.), calciumchannel blockers (such as nifedipine), colchicine, fibroblast growthfactor (FGF) antagonists, fish oil (omega 3-fatty acid), histamineantagonists, lovastatin (an inhibitor of HMG-CoA reductase, acholesterol lowering drug, brand name Mevacor® from Merck & Co., Inc.,Whitehouse Station, N.J.), monoclonal antibodies (such as those specificfor Platelet-Derived Growth Factor (PDGF) receptors), nitroprusside,phosphodiesterase inhibitors, prostaglandin inhibitors, suram in,serotonin blockers, steroids, thioprotease inhibitors,triazolopyrimidine (a PDGF antagonist), and nitric oxide. An example ofan antiallergic agent is permirolast potassium. Other biologically orpharmacologically active substances or agents that may be used includenitric oxide, alpha-interferon, genetically engineered epithelial cells,and dexamethasone. In other examples, the biologically orpharmacologically active substance is a radioactive isotope forimplantable device usage in radiotherapeutic procedures. Examples ofradioactive isotopes include, but are not limited to, phosphorus (P³²),palladium (Pd¹⁰³), cesium (Cs¹³¹), Iridium (I¹⁹²) and iodine (I¹²⁵).While the preventative and treatment properties of the foregoingbiologically or pharmacologically active substances are well-known tothose of ordinary skill in the art, the biologically orpharmacologically active substances are provided by way of example andare not meant to be limiting. Other biologically or pharmacologicallyactive substances are equally applicable for use with the disclosedmethods and compositions.

Further, a carrier may be used with the biologically orpharmacologically active substance. Examples of suitable carriersinclude, but are not limited to, urea, ethanol, acetone,tetrahydrofuran, dymethylsulfoxide, a combination thereof, or othersuitable carriers known to those skilled in the art. Still further, asurfactant may be formulated with the biologically or pharmacologicallyactive substance and the solvent to aid elution of the biologically orpharmacologically active substance.

Stent 500 may be used conventionally in blood vessels of the body tosupport such a vessel after an angioplasty procedure. It is known thatcertain biologically or pharmacologically active substances eluted fromstents may prevent restenosis or other complications associated withangioplasty or stents. Stent 500 may alternatively be used in otherorgans or tissues of the body for delivery of biologically orpharmacologically active substance to treat tumors, inflammation,nervous conditions, or other conditions that would be apparent to thoseskilled in the art.

While various embodiments of the present invention have been describedabove, it should be understood that they have been presented by way ofillustration and example only, and not limitation. It will be apparentto persons skilled in the relevant art that various changes in form anddetail can be made therein without departing from the spirit and scopeof the invention. Thus, the breadth and scope of the present inventionshould not be limited by any of the above-described exemplaryembodiments, but should be defined only in accordance with the appendedclaims and their equivalents. It will also be understood that eachfeature of each embodiment discussed herein, and of each reference citedherein, can be used in combination with the features of any otherembodiment. Furthermore, there is no intention to be bound by anyexpressed or implied theory presented in the preceding technical field,background, brief summary or the detailed description. All patents andpublications discussed herein are incorporated by reference herein intheir entirety.

1-15. (canceled) 16: A method of forming a stent comprising the stepsof: shaping a composite wire into a stent pattern, wherein the compositewire comprises a core member and an outer member, wherein the outermember is a nitinol material and the core member is a material havingsufficient stiffness to hold the nitinol outer member in the stentpattern prior to a heat treatment step; heat treating the composite wirein the stent pattern; providing openings through the outer member to alumen of the outer member; processing the composite wire such that thecore member is removed from the outer member without adversely affectingthe outer member. 17: The method of claim 16, wherein the step ofproviding openings through the outer member comprises laser drillingopenings through the outer member. 18: The method of claim 16, whereinthe core member comprises a material selected from the group consistingof tungsten and molybdenum, and wherein the step of processing thecomposite wire to remove the inner member comprises exposing thecomposite wire to xenon difluoride gas. 19: The method of claim 16,further comprising the step of filling the lumen of the outer memberwith a biologically or pharmacologically active substance after the coremember has been removed. 20: The method of claim 19, wherein thesubstance is selected from the group consisting of antineoplastic,antimitotic, antiinflammatory, antiplatelet, anticoagulant, anti fibrin,antithrombin, antiproliferative, antibiotic, antioxidant, andantiallergic substances as well as combinations thereof.